Myocardial Mechanics in Patients With Normal LVEF and Diastolic Dysfunction

JACC: CARDIOVASCULAR IMAGING

-, NO. -, 2019

VOL.

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

STATE-OF-THE-ART PAPER

Myocardial Mechanics in Patients With Normal LVEF and Diastolic Dysfunction Christopher M. Bianco, DO, Peter D. Farjo, MD, Yasir A. Ghaffar, MD, Partho P. Sengupta, MD, DM

ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is a complex clinical entity that is poorly understood yet present in up to 5.5% of the general population. Proven therapies for this disorder are lacking, even though it has a similar prognosis to that of heart failure with reduced ejection fraction (HFrEF). Innovative imaging techniques have provided in-depth understanding of the unique pattern of left ventricular mechanics in patients with HFpEF who progress through preclinical (Stages A to B) and clinical (Stages C to D) American College of Cardiology/American Heart Association heart failure stages. This review highlights the mechanical basis of this disorder from the cellular and myofiber level to chamber dysfunction. As each chamber of the heart is examined, specific biomarkers and echocardiographic parameters with diagnostic and prognostic values are discussed. Finally, novel phenotyping methods including machine learning are reviewed that integrate these mechanics into clinical groups to advise and treat patients. (J Am Coll Cardiol Img 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.

H

eart failure with preserved ejection fraction

evolution

(HFpEF) is responsible for approximately

(Stages C and D) occurs with significant heteroge-

of

subsequent

clinical

heart

failure

one-half of all heart failure hospitaliza-

neity of cardiac structural and functional abnor-

tions, with a mean survival rate similar to those

malities. Recent emphasis in bioinformatics-driven

with heart failure with reduced ejection fraction

platforms has ushered in new ways to integrate

(HFrEF) (1). The overall prevalence of HFpEF is be-

heterogeneous information and may help to identify

tween 1.1% and 5.5% in the general population and

individualized phenotypes within this heteroge-

may be as high as 10% in elderly women (2,3). With

neous spectrum. The recognition of subtle abnor-

an increasing burden of comorbid states and the

malities

growing elderly population, the prevalence of HFpEF

individuals may lead to earlier, more aggressive risk

is projected to increase.

mitigation

of

myocardial strategies.

mechanics

Furthermore,

in

at-risk

phenotype-

Common disorders such as hypertension, dia-

specific therapy informed by myocardial mechanics

betes, kidney disease, and obesity (Stage A) pre-

may prove advantageous when making treatment

dispose to early subclinical structural disease (Stage

decisions. This review focuses on the changes in

B), which is now present in one-fourth of the adult

myocardial mechanics that occur through the heart

U.S. population (4). Recent data suggest myocardial

failure

mechanics early in the disease state can predict the

research relating myocardial mechanics to diagnosis

evolution of heart failure phenotypes. However, the

and prognosis.

stages

and

presents

the

contemporary

From the Division of Cardiology, West Virginia University Heart and Vascular Institute, Morgantown, West Virginia. Dr. Bianco is a private investigator for an AstraZeneca trial. Dr. Sengupta is an advisor to HeartSciences, Ultromics, and Hitachi Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Sherif Nagueh, MD, served as Guest Editor for this paper. Manuscript received October 22, 2018; revised manuscript received December 10, 2018, accepted December 10, 2018.

ISSN 1936-878X/$36.00

https://doi.org/10.1016/j.jcmg.2018.12.035

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Myocardial Mechanics in HFpEF

ABBREVIATIONS

LEFT VENTRICULAR MYOCARDIAL

deformation and creates a centrifugal force for

AND ACRONYMS

MECHANICS: CELL- TO

aspirating left atrial blood, facilitating effective

ORGAN-SPECIFIC CHANGES

GCS = global circumferential

diastolic filling. Stage A. Stage A disease, defined by the presence of

strain

CELLULAR DYSFUNCTION IMPACT ON LV

risk factors without overt structural disease by

strain

MECHANICS. The ultrastructural and cellular

traditional markers, is present in approximately

GRS = global radial strain

basis for the development of abnormal

one-fifth of the adult population (13). Although con-

myocardial mechanics during the transition

ventional

preserved ejection fraction

from risk factor acquisition to structural dis-

subendocardial dysfunction is commonly present and

HFrEF = heart failure with

ease remain largely unknown. Hypertension

evident by reduced GLS. The prevalence of reduced

reduced ejection fraction

is associated with early transtubule disorga-

global longitudinal deformation in asymptomatic

LAScd = left atrium strain

nization and impaired calcium cycling, which

metabolic disease has been reported to range from

during conduit phase

leads to reductions in longitudinal, circum-

37% to 54% (14). An early GLS reduction may be found

LASct = left atrium strain

ferential, and radial strain, linking declining

with pre-hypertensive patients and higher cumula-

cell ultrastructure and abnormal myocardial

tive exposure to elevated blood pressure from young

mechanics (5). These changes may occur

adulthood to middle age is associated with lower

prior to or concurrently with the develop-

longitudinal strain rate (15,16). Despite decreased

ment of hypertrophy and typically precede

longitudinal mechanics, the EF remains preserved

the formation of cardiac fibrosis (Figure 1).

due to retained circumferential and twist mechanics

Also, insulin resistance has been associated

provided by the relatively unaffected subepicardial

with reduced longitudinal strain in patients without

layer. Furthermore, a reduction in GLS may be pres-

structural heart disease, implicating alterations of

ent prior to the onset of LV remodeling and hyper-

fatty acid and glucose metabolism in the pathogen-

trophy (17). Although tissue Doppler-derived early

esis of impaired myocardial mechanics (6). Addi-

diastolic longitudinal mitral annular velocities are

tionally, multiple biomarkers have been identified

often impaired in early stages of the disease, reduced

that may influence HFpEF development. Longitudi-

longitudinal strain may exist despite the fact that

nal strain and torsion independently correlate with

several of the conventional Doppler- and tissue

serum

Doppler-derived parameters of diastolic function are

GLS = global longitudinal

HFpEF = heart failure with

during contractile phase

LASr = left atrium strain during reservoir phase

PH = pulmonary hypertension RVLS = right ventricle longitudinal strain

levels

of

tissue

inhibitor

of

matrix

imaging

biomarkers

may

be

absent,

metalloproteinase-1 in patients with hypertension

normal (18) (Figure 1).

and HFpEF, suggesting that impaired collagen turn-

Stage B. Prolonged risk factor exposure leads to

over affecting the integrity of the extracellular matrix

increasing subendocardial dysfunction, apparent by

may play a role in early deformation changes that

further

precede

ventricular

lengthening, and suction performance. These me-

the

development

of

left

reductions

in

longitudinal

shortening,

(LV) hypertrophy (7). Elevated levels of serum

chanical changes, evident by subclinical systolic and

angiotensin-converting enzyme are also associated

diastolic dysfunction, as well as by remodeling and

with decreased longitudinal strain and impaired twist

hypertrophy, represent the transition to Stage B dis-

mechanics (8). Levels of galectin-3, a binding protein

ease. Early in the disease course, EF is preserved

secreted by activated macrophages to promote

given the dominant contribution of the subepicardial

fibrosis and pro-collagen deposition in the extracel-

layer to circumferential and LV twist deformation. If

lular matrix, are elevated in diabetic patients and may

compensation is not possible due to concomitant

be associated with diminished global longitudinal

dysfunction of the subepicardial region, the EF falls

strain (GLS) (9). HFpEF- associated reductions in GLS

and ventricular dilation ensues (19). In those patients

have been correlated with increased myocardial

who are able to compensate, myocardial hypertrophy

fibrosis and increased natriuretic peptide levels

of the subepicardial region may occur in an attempt to

(10,11).

reduce subendocardial wall stress and preserve LVEF (20).

FIBER-

TO

myocardial

CHAMBER-LEVEL

layer

circumferential,

DYSFUNCTION. Each

contributes

are

associated

with

incremental

onset of HFpEF (21). Longitudinal strain becomes

shortening, while subepicardial fiber contraction

concordantly worse in renal disease with deteriora-

contributes to the circumferential and twisting

tion of estimated glomerular filtration rate, hyper-

deformation

of

relea-

tension with increasing duration of uncontrolled

ses

mechanical

systolic

blood pressure, and diabetes with poorer control of

(12).

The

burden,

endocardial fibers largely contribute to longitudinal

LV

motions.

Increasing age, along with a greater comorbid disease

impairment in myocardial deformation and clinical

the

radial

longitudinal, sub-

stored

and

to

Untwisting

energy

from

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Myocardial Mechanics in HFpEF

F I G U R E 1 Natural History: Temporal Evolution of Myocardial Mechanics

Stage A

Stage B

Stage C

Stage D

HTN DM CKD CAD Obesity Cellular Dysfunction LVH Fibrosis Wall Stress LV Global Longitudinal Strain LV Global Circumferential Strain LV Reservoir Strain RV Free Wall Longitudinal Strain Overt Diastolic Dysfunction Time

CAD ¼ coronary artery disease; CKD ¼ chronic kidney disease; DM ¼ diabetes mellitus; HTN ¼ hypertension; LA ¼ left atrium; LV ¼ left ventricle; RV¼ right ventricle.

blood glucose (22–24). These associations provide a

the

plausible link between control of the comorbid dis-

HFpEF (29,30).

myocardial

mechanics

found

in

advanced

ease state, failing myocardial mechanics, and progression along the HF continuum.

DIAGNOSTIC VALUE OF LV MECHANICS.

Stages C and D. With further clinical deterioration to

mechanics: correlates to invasive hemodynamics. Resting

Stage C heart failure, global circumferential strain

deformation has been used to predict HFpEF-

(GCS), LV twist, and twist/untwist rates may remain

associated invasive hemodynamics and exercise he-

Role of resting

normal or even increase to supranormal values (25)

modynamics (Table 1). A ratio of mitral E to global

(Figure 2). Although GCS, LV twist, and twist/untwist

longitudinal strain rate during isovolumic relaxation

rates may remain normal or increase early in HFpEF,

time (SRIVRT ) can be used to predict LV filling pres-

times to peak twist and peak untwist are often

sures with reasonable accuracy, particularly in pa-

delayed, which affects both systolic and diastolic

tients with intermediate E/e 0 ratios and those with

performance (26). Additionally, Stage C patients have

normal EF (31,32). Reduced GLS and increased GCS at

significant reductions in GLS and increased extracel-

rest are associated with a significant increase in pul-

lular volume fraction compared to those in Stage B

monary capillary wedge pressure from rest to peak

(27). Despite impaired resting longitudinal deforma-

exercise, making the GCS/GLS ratio a potential pre-

tion, those in Stage B can augment longitudinal me-

dictor of exercise-induced pulmonary venous hyper-

chanics during exertion to a greater extent than those

tension (33).

in Stage C (Central Illustration). This may explain the

Role of resting mechanics: correlates to functional

initial onset of exertional symptoms during the

capacity. Resting deformation has been used to pre-

transition from Stage B to C (28). Progressive deteri-

dict HFpEF-associated exercise limitations (Table 1).

oration of circumferential, radial, and longitudinal

Several investigators have reported associations

strain, as well as LV twist and untwist, characterize

with GLS and subjective assessments of exercise

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F I G U R E 2 Conventional and Speckle Tracking Echocardiographic Parameters of Myocardial Mechanics in HFpEF

(A) Transmitral Doppler showing a restrictive filling pattern suggestive of elevated left atrial pressure. (B) Tissue Doppler recordings of a severely reduced septal mitral annular velocity. (C) Reduced LV global longitudinal strain of 15.2%, commonly found throughout the HFpEF continuum. (D) Circumferential strain is preserved in this patient, which is commonly encountered in Stage C HFpEF. (E) LA reservoir strain reduced at 12.5%, LA conduit strain reduced at 10.5%, and LA booster pump reduced at 4%, typical of advanced Stages C to D disease. (F) Reduced RV global longitudinal strain of 14.5%, commonly encountered in clinical HFpEF. HFpEF ¼ heart failure with preserved ejection fraction; other abbreviations in Figure 1.

symptoms and functional class. Cardiopulmonary

incompetence and ventriculo-arterial uncoupling, in

stress testing allows for an objective functional

addition to peripheral factors.

assessment, and resting GLS and pulmonary arterial

Role of exercise mechanics. Deformation imaging dur-

systolic pressure have been found to correlate inde-

ing exercise has been used in the diagnosis of HFpEF.

pendently with peak oxygen consumption in HFpEF

Normally, increased deformation occurs with exer-

patients (34). However, other investigators have

cise; however, those with myocardial diseases may

failed to demonstrate a relationship between resting

have less robust exercise-associated deformation.

GLS and peak oxygen consumption. Thus, the role of

HFpEF patients exhibit significantly reduced im-

resting GLS in predicting objective measurements of

provements in GLS and right ventricle (RV) longitu-

functional

dinal systolic function during exercise than patients

capacity

remains

unresolved

(35).

A

possible explanation for this discrepancy relates to

without HFpEF (36) (Central Illustration). Mitral

the multitude of mechanisms leading to exertional

annular systolic and diastolic velocities, systolic left

limitations

ventricular rotation, and early diastolic untwist on

in

HFpEF

including

chronotropic

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C E N T R A L IL L U ST R A T I O N Pattern of Myocardial Mechanics During Rest and Exercise in Different Stages of HFpEF

Bianco, C.M. et al. J Am Coll Cardiol Img. 2019;-(-):-–-.

(A) Stage A is characterized by normal or nearly normal resting LV and RV GLS (blue), normal or nearly normal LA reservoir function, and normal LA conduit and booster functions (blue). All parameters augment adequately with exercise (red). (B) Stage B is characterized by mildly depressed resting LV and RV GLS, mildly depressed LA reservoir and conduit function, and increased LA booster function (blue). LV and RV GLS augment to nearly normal with exercise (red). LA conduit function increases significantly with exercise (red). (C) Stage C is characterized by moderately depressed resting LV and RV GLS (blue) with significantly impaired augmentation during exercise (red). Resting LA reservoir, conduit function, and booster function are impaired at rest (blue), and all parameters augment to suboptimal levels with exercise (red). (D) Stage D is characterized by markedly depressed resting LV and RV GLS (blue) with little augmentation during exercise (red). Similarly, all atrial functional phases are impaired at rest (blue) with little augmentation during exercise (red). GLS ¼ global longitudinal; LA ¼ left atrium; LV ¼ left ventricle; RV ¼ right ventricle.

exercise correlated with peak oxygen consumption

more aggressive modification of risk factors (40)

(37). Impaired GLS during exercise has been inde-

(Table 1). In more advanced clinical HF, reduction of

pendently associated with an increased occurrence of

GLS provides incremental prognostic value to stan-

all-cause mortality and HF hospitalizations (38). A

dard prognostic factors. In the TOPCAT (Treatment of

reduced GLS rate on exertion provides prognostic

Preserved Cardiac Function Heart Failure With

value independent of and incremental to clinical data

an Aldosterone Antagonist; NCT00094302) trial,

and natriuretic peptides. Furthermore, the ability of

impaired longitudinal strain (GLS >15.8%) was

GLS rate to predict outcomes on exertion exceeded its

present in 52% of patients and predictive of both

prognostic value at rest (39).

cardiac death and HF hospitalizations (41). A recent large meta-analysis including 22 studies likewise

PROGNOSTIC

VALUE

OF

LV

MECHANICS. Preclinical

found that a reduction in GLS was associated with a

reduction of GLS is independently associated with a

hazard ratio of 2.14 for cardiovascular mortality and

worse clinical prognosis and thus serves as an

1.94 for HF hospitalization, even after adjusting for

important imaging biomarker that should prompt

multiple clinical and echocardiographic variables

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(42). More than three-fourths of patients hospitalized

Stage A. Preclinical atrial dysfunction is characterized

with decompensated HFpEF have abnormal GLS

by reduced reservoir and conduit function, while

(GLS >16%). Hospitalized HFpEF patients with

atrial contractile function remains normal (52).

abnormal GLS are more likely to be elderly and female

Reduced LA deformation is a common finding in the

and have hypertension. Impaired GLS during hospi-

general population and is associated with various

talization is independently associated with mortality

degrees of preclinical dysfunction (53). The LA walls

and rehospitalization at 30 days (43). Following

are significantly thinner than the LA and therefore

hospitalization, impaired GLS is also associated with a

may be affected by various pathologies earlier than

shorter time to mortality over the next 3 years (44).

the LV; furthermore, the LA may be less apt to undergo compensatory changes without undergoing

LEFT ATRIAL MYOCARDIAL MECHANICS:

gross structural remodeling and enlargement. LA

CELL- TO ORGAN-SPECIFIC CHANGES

strain abnormalities occur prior to overt LA enlarge-

CELLULAR DYSFUNCTION IMPACT ON LA MECHANICS.

Atrial cellular insults lead to functional, electrical, and structural remodeling that may be appreciated with deformation imaging far sooner than enlargement that is detected on volume-based imaging techniques. Left atrial (LA) wall fibrosis, commonly found in HFpEF, is inversely related to LA strain and

strain

rate

(45).

Soluble

suppression

of

tumorigenicity-2 receptor (ST2), a novel biomarker of pro-fibrotic burden, is inversely associated with LA reservoir strain, but not with LA size, LV geometry, or systolic or diastolic LV function (46). Diabetes independently predicts worse LA reservoir and contractile

ment, and reduced reservoir function may occur in the absence of overt diastolic dysfunction or LV hypertrophy (54). Stage B. Progressive subclinical dysfunction is associated with abnormal reservoir and conduit functions, but atrial contractile deformation increases (53) (Central Illustration). Increased LA contractile deformation appears to be a compensatory mechanism to increase late filling, mirroring the mitral inflow pattern typical of abnormal relaxation. Furthermore, an increase in conduit strain during periods of tachycardia or exertion may also compensate for reduced reservoir function.

strain, suggesting accumulation of glycated end

Stages C and D. Clinical HF onset occurs when atrial

products, and metabolic changes may lead to signifi-

contractile function fails to compensate for reservoir

cant LA dysfunction (47). In patients at risk for

and conduit dysfunction (55) (Figure 2). Typically, LA

HFpEF, coronary microvascular dysfunction is asso-

contractile strain is abnormal at this stage, but some

ciated with diastolic dysfunction and LA strain

ambulatory HFpEF patients may continue to exhibit

impairment independent of age, sex, and common

contractile strain in the normal range. A failure of

comorbidities, but only marginally related to LV

compensatory conduit function in the setting of

strain, suggesting LA myocardial mechanics may be

impaired reservoir function may also lead to early

more susceptible to coronary microvascular disease

exercise-induced symptoms (56). Those with atrial

than LV myocardial mechanics (48).

fibrillation may have earlier onset of symptoms given

FIBER- TO CHAMBER-LEVEL DYSFUNCTION. The LA is

failure of atrial contractile compensation, and the

complex and made up of 2 muscular layers. The sub-

adequacy of compensatory conduit function is a large

endocardial layer is composed of longitudinal fibers,

determinant

while the subepicardial layer is composed of circum-

symptomatic HF with preserved EF is characterized

ferential fibers (49). The LA functions as a reservoir

by a decrement in all 3 atrial strain phases (58)

for pulmonary venous return during ventricular sys-

(Central Illustration).

of

symptom

onset

(57).

Advanced

tole, as a conduit for pulmonary venous return during

Finally, LA reservoir strain progressively decreases

early ventricular diastole, and as a booster pump that

with increasing grades of diastolic dysfunction (59).

LA

Unlike left atrial volume index and E/e 0 ratio, LA

deformation does not occur in isolation, and the inter-

reservoir strain consistently decreases and remains

related nature of atrial and ventricular deformation

significantly different among all sequential diastolic

must be considered (50). Contractile function is

dysfunction grades (Figure 1). Therefore, LA reservoir

dependent on both intrinsic atrial contractility and

strain may help to stratify patients at risk with inde-

afterload imposed by the LV in late diastole. Impaired

terminate

longitudinal deformation and diastolic dysfunction

recommendations.

often accompany impaired atrial deformation; there-

DIAGNOSTIC VALUE OF LA MECHANICS.

fore, controversy exists concerning the origin and

resting mechanics: correlates with functional capacity.

independent relevance of LA strain abnormalities (51).

Preclinical reductions in LA reservoir strain are

augments

late

ventricular

filling.

However,

diastolic

function

based

on

current Role of

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T A B L E 1 Prevalence of Abnormal LV Strain and Diagnostic and Prognostic Utility

First Author, Year (Ref. #)

HFpEF HFrEF Control/Confirm

Objective

Strain Parameters

Clinical Relevance

E/SRIVR <236 cm predicts PCWP >15 mmHg; E/SRIVR >300 predicts PCWP >15; HFrEF: E/SRIVR >1,500 predicts PCWP >25

Global SRIVR correlates with relaxation E/SRIVR can diagnose elevated LVFP

To examine myocardial deformation and twist in HF and elucidate the HFpEF mechanism

LS Y, RS Y, CS Y, Y Twist LS Y, RS Y n CS, n Twist

Strain patterns different in HFpEF and HFrEF

To assess the impact of LVFP on systolic and diastolic myocardial mechanics in heart diseases and HFpEF

LS Y, RS Y, CS Y, Y twist - predicts LV Directional strain correlates with pre-A >15 mm Hg elevated filling pressures in HFpEF

Wang et al., 2007 (31)

20

30

7 (canines)/24 To assess diastolic strain rate for LV relaxation and LVFP

Wang et al., 2008 (25)

20

30

17

Nguyen et al., 2010 (30)

60

-

-

Yip et al., 2011 (29)

112

175

60

To compare LV performance with LS Y, RS Y, CS Y contractility among HFpEF, HFrEF, and Y LV contractility – load control patients independent -

Donal et al., 2012 (36)

21

-

15

To compare myocardial dynamics at rest vs. at submaximal exercise in HFpEF patients

Kraigher-Krainer et al., 2014 (11)

219

23

50/44

Shah et al., 2015 (41)

269

-

447

Hasselberg et al., 2015 (34)

37

57

Wang et al., 2015 (38)

80

Hatipoglu et al., 2015 (32)

LV GLS Y, RV GLS Y

To determine the frequency and magnitude LS Y, CS Y of impaired LV contractility in HFpEF patients

Reduced deformation reflects impaired myocardial contractility in HFpEF Impaired GLS of LV and RV at submaximal exercise reflects myocardial dysfunction in HFpEF Abnormal strain parameters significant correlation with elevated NT-pro BNP in HFpEF

To determine whether LS predicts CV outcomes in HFpEF

LS Y

Y LS is an independent predictor of MACE

6

To assess exercise capacity in systolic and diastolic myocardial dysfunction patients

LV and RV GLS Y, LV and RV GLS Y

Y LV GLS predicts peak VO2 <20 ml/ kg/min superior to LVEF, RV strain and E/E0

-

-

To assess prognostic value of echo parameters in HFpEF patients

GLS Y

Impaired GLS during exercise is an independent predictor of allcause mortality and hosp.

65

-

-

To assess LV and LA strain and determine whether strain rate can predict LVEDP

SRIVR [, [ LVEDP, GLS Y, PALS Y

SRIVR can diagnose elevated LVEDP in HFpEF patients

Kosmala et al., 2016 (28)

207

-

-

To compare contractile reserve, LV GLS Y ventriculoarterial coupling reserve, and Stage C3 >C2 > C1 > B chronotropic response to the LA strain Y -HFpEF as above progression of HFpEF RV Strain Y -HFpEF as above

Kosmala et al., 2017 (39)

205

-

-

To determine the prognostic value of GLS during exercise in HFpEF

GLS Y, GSR Y, Abn DR Y

Y exertional GLS rate and AbnDR was associated with worse prognosis

DeVore et al., 2017 (35)

187

-

-

To examine the association of GLS in HFpEF with functional capacity and quality of life

GLS Y

LV GLS $-12.9% associated with Y VO2 and [ BNP

Morris et al., 2017 (42)

2,284

-

2,302

To confirm whether GLS is altered in HFpEF GLS Y (meta-analysis)

Y GLS significantly lower among HFpEF patients

Buggey et al., 2017 (43)

463

-

-

To assess the association between LV GLS GLS Y and outcomes in patients hospitalized with HFpEF

High prevalence of Y GLS in hospitalized HFpEF patients and associated with worse 30-day outcomes

Biering-Sørensen et al., 2017 (33)

85

-

-

To examine whether LS and CS are associated with LVEDP in HFpEF patients during exercise

LS Y CS [

Higher CS/LS ratio was predictive of elevation in PCWP with exercise

-

-

551

To study the effects of T2DM and other risks in Stage A HF

GLS Y

T2DM-SAHF patients had worse LV function, exercise capacity, and prognosis compared to those with different HF risk factors.

Wang et al., 2018 (40)

GLS (GLS), LA strain, RV strain predicts progression of HFpEF stage

Abn DR ¼ abnormal diastolic reserve; B ¼ stage B heart failure; C1 ¼ stage C1 heart failure; C2 ¼ stage C2 heart failure; C3 ¼ stage C3 heart failure; CS ¼ circumferential strain; CV ¼ cardiovascular; E/SRIVR ¼ Ratio of mitral E to global longitudinal strain rate during isovolumic relaxation time; GLS ¼ global longitudinal strain; GSR ¼ global longitudinal strain rate; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; LA ¼ left atrium; LS ¼ longitudinal strain; LV ¼ left ventricle; LV pre-A ¼ pre-A wave pressure; LVEDP ¼ LV end-diastolic pressure; LVEF ¼ left ventricular ejection fraction; LVFP ¼ LV filling pressure; MACE ¼ major adverse cardiac event; PALS ¼ peak atrial longitudinal strain; PCWP ¼ pulmonary capillary wedge pressure; RS ¼ radial strain; RV ¼ right ventricle; SAHF ¼ Stage A heart failure; SRIVR ¼ longitudinal strain rate during isovolumic relaxation time; T2DM ¼ type 2 diabetes mellitus; VO2 ¼ maximal oxygen uptake.

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T A B L E 2 Diagnostic and Prognostic Utility of LA Strain

First Author, Year (Ref. #) HFpEF HFrEF Control

Objective

Strain Parameters

Clinical Relevance

Santos et al., 2014 (58)

135

-

40

To study impaired LA function in HFpEF

LA reservoir, pump and conduit function Y

HFpEF patients had lower LA reservoir, conduit, and pump function than controls

Sanchis et al., 2015 (55)

63

32

43

To analyze LA function in new onset HF as an outpatient

LS Y, LA-SRa Y, LA-SRs Y, LA-SRe Y

Abnormal LA strain parameters were diagnostic for HF and more commonly present in HFrEF than HFpEF

Freed et al., 2016 (61)

308

-

-

To examine importance of LA strain

LA strain Y LV and RVLS Y

LA strain <31% showed linear relationship with MACE in HFpEF

Sanchis et al., 2016 (66)

74

34

46

To assess prognostic role of LA strain in outpatient HF patients

LASRa Y

LASRa correlates with BNP, LAVI, LV indexed volume, and LV GLS

Santos et al., 2016 (51)

357

-

-

To assess prognostic relevance of LA strain in HFpEF

Y LA peak strain / Y LVEF, Y LV-GLS, [ LVEDP, Y RV function, [ PASP, [ BNP

LA dysfunction in HFpEF is associated with higher risk of HF hospitalization

von Roeder et al., 2017 (56)

22

-

12

Characterize LA function in HFpEF during exercise

LA volume [ LA conduit, þ and -ve strain Y

LA strain Y was strongly correlated with VO2max Y

Morris et al., 2017 (60)

-

-

517

To assess usefulness of adding LA strain to LAVI in detection of LVDD

LA strain Y

Adding LA reservoir strain <23% increases the sensitivity of conventional echo parameters to detect DD

20

49

32

To determine if LA impairment during LA strain [ exercise and recovery exercise in HF effects RV-PA uncoupling and ventilation inefficiency LA strain no change

Sugimoto et al., 2017 (62)

Impaired LA-strain response leads to RVPA uncoupling and exercise ventilation inefficiency

BNP ¼ B-type natriuretic peptide; DD ¼ diastolic dysfunction; LA ¼ left atrium; LASRa ¼ LA strain rate post A-wave; LA-SRe ¼ LA strain-rate E-wave; LA-SRs ¼ LA systolic strain rate; LAVI ¼ LA volume index; LVDD ¼ left ventricular diastolic dysfunction; LV GLS ¼ LV global longitudinal strain; PASP ¼ pulmonary artery systolic pressure; RV-PA ¼ right ventriculo-pulmonary arterial; other abbreviations as in Table 1.

associated with the subsequent development of

strongly predictive of adverse cardiac events and

HFpEF and worse New York Heart Association

death (64) (Table 2). In an at-risk population,

(NYHA) functional class, even when LA volume index

impaired LA reservoir function is commonly found

is normal (60). Abnormal LA deformation is useful in

prior to LA enlargement and is associated with an

differentiating non-HF-related dyspnea from HFpEF

increased risk of HF hospitalization at 2 years, even

and relates to onset of symptoms in the progression

adjusting for age and sex and in patients with

from Stage B to Stage C disease (55). In patients with

normal LAVI (60). Therefore, LA strain serves as a

known HFpEF, decreased resting LA reservoir strain

sensitive marker of subclinical dysfunction. Risk

is associated with decreased peak oxygen consump-

mitigation strategies have been shown to lead to

tion on cardiopulmonary stress testing (61).

improvements in LA strain, although the impact

Role of exercise mechanics. LA reservoir strain increases during exercise normally, but to a lesser extent

in

HFpEF

patients

(Central

Illustration).

Impaired LA reservoir response to exercise appears to be a key trigger for RV-pulmonary arterial uncoupling and exercise ventilatory inefficiency (62). Right ventricle-pulmonary arterial uncoupling and LA strain at rest, exercise, and recovery significantly correlate with pulmonary arterial systolic pressure/ tricuspid annular peak systolic excursion, as well as ventilation versus carbon dioxide slope. Conduit function during exercise correlates with tau, as well as peak oxygen consumption on cardiopulmonary exercise

testing

(63).

Therefore,

alterations

in

conduit function are likely important determinants of exercise capacity.

on

prognosis

and

progression

to

HF

are

not

known (65). Impaired LA contractile strain rate on initial HFpEF diagnosis predicts subsequent HF hospitalizations or death (66). In known HFpEF patients, LA reservoir strain

independently

predicts

the

composite

endpoint of HF hospitalization and all-cause mortality, even after adjustment for potential clinical and cardiac mechanical confounders, including LV GLS and filling pressures (46). Furthermore, LA reservoir strain was found to outperform LV longitudinal strain and RV free wall strain in its prognostic and discriminative value above and beyond conventional risk markers for prediction of HF hospitalization (61).

RIGHT HEART MYOCARDIAL MECHANICS

PROGNOSTIC VALUE OF LA MECHANICS. In hyper-

tensive patients at risk for diastolic dysfunction

Right heart dysfunction is common throughout the

and

clinical

HF,

decreased

LA

contractile

function

is

progression

of

asymptomatic

diastolic

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T A B L E 3 Diagnostic and Prognostic Ability of RV Strain

First Author, Year (Ref. #)

HFpEF HFrEF Control

Objective

Strain Parameters

Clinical Relevance

Morris D et al., 2011 (73)

201

-

364

To study RV strain in HFpEF

RV GLS Y, RV-SRe Y HFpEF

RV-SRe and RV-strain are frequently seen in HFpEF patients

Melenovsky et al., 2014 (81)

96

-

46

To assess variables of RV dysfunction in HFpEF

Not done

33% of HFpEF patients had RV dysfunction compared with controls, which is associated with worse outcomes

Hasselberg et al., 2015 (34)

37

-

57

To study GLS during exercise in HFpEF and HFrEF

LV -GLS Y, RV – GLS Y

Impaired RV strain and LV strain are associated with VO2max <20 ml/kg/min in HFpEF patients.

Morris et al., 2017 (80)

218

208

454

Detect subtle RV dysfunction in HF patients by using strain

RV-GLS Y, RV fee wall strain Y

Subtle RV systolic dysfunction easily determined by strain despite normal RV FAC TAPSE and RV S0

FAC ¼ fractional area change; GCS ¼ global circumferential strain; Global LAB ¼ peak atrial longitudinal booster strain during atrial contraction; Global LAS ¼ peak atrial longitudinal strain during ventricular systole; GSRl ¼ reduced global longitudinal strain rate; LASr ¼ LA strain during reservoir phase; PASP ¼ pulmonary artery systolic pressure; PCWP ¼ pulmonary capillary wedge pressure; PH ¼ pulmonary hypertension; RVLS ¼ RV longitudinal strain; RV-SRe ¼ right ventricle global longitudinal early-diastolic strain rate; TAPSE ¼ tricuspid annular plane systolic excursion.

dysfunction to overt HF. At least one-fifth of HFpEF

patients than in asymptomatic control patients (74).

patients have RV dysfunction by conventional pa-

A distinct HFpEF phenogroup exists, characterized

rameters and almost one-half by RV deformation

by extensive remodeling with prominent pulmonary

indices (61,67,68). Unfortunately, far less data per-

hypertension and right HF (75). This phenogroup

taining to right heart myocardial mechanics in HFpEF

more often includes elderly patients with chronic

are available; nonetheless, it is an evolving area of

kidney disease and appears to be at particularly

study.

high risk.

FIBER- TO CHAMBER-LEVEL DYSFUNCTION. The thin

Right

right ventricular free wall is composed predomi-

hypertension. At least two-thirds of patients will

heart

dysfunction

secondary

to

pulmonary

nantly of transversely oriented fibers. Circumferen-

exhibit evidence of resting pulmonary hypertension

tial compression of the RV free wall results in a

(PH), and pulmonary pressures may increase sub-

bellows motion contributing 20% of RV systolic

stantially with exercise, leading to conditional RV

function. Shearing forces of the oblique interven-

failure (67,76). RV dilation is present in almost one-

tricular septal fibers result in systolic twisting of the

third of cases, and altered septal geometry impairs

base toward the apex (69). Interventricular septal

septal

mechanics are responsible for right ventricular lon-

Although the RV has been conventionally viewed as a

gitudinal motion, contributing 80% of RV systolic

nonessential

function. Infundibular fiber contraction results in

increasingly important when faced with the pulsatile

a minor peristalsis-like contribution to late RV

resistive afterload characteristic of HFpEF-related

ejection (70).

PH (77).

Stage A and B patients with metabolic syndrome

contractility

and

conduit,

RV

RV

performance

performance

(67).

becomes

Right heart dysfunction independent of pulmonary

and obesity commonly exhibit subclinical biven-

hypertension. Conventionally,

tricular dysfunction with preserved EF (Figure 1).

ventricular-pulmonary arterial (RV-PA) uncoupling

Increasing body mass index is associated with

were thought to be the exclusive causes of HFpEF-

further decrements in right ventricular longitudinal

associated

strain (RVLS) in overweight and obese subjects

concomitantly impacting LV mechanics may lead to

without overt heart disease, independent of sleep

deterioration in RV mechanics. LV GLS was found to

apnea (71). Similarly, diabetic and hypertensive

be the most important independent predictor of RV

patients frequently exhibit subclinical RV deforma-

longitudinal function, in contrast to pulmonary arte-

tion impairments (72). With disease progression to

rial systolic pressure, which was only weakly related

Stages C and D, almost one-half of patients have

to RV dysfunction (73). This concept was substanti-

RV dysfunction by deformation indices (61). Both

ated by another study in which RV dysfunction by

RV global longitudinal early diastolic strain rate

both tricuspid annular plane systolic excursion

and

significantly

(TAPSE) and RVLS were independently associated

impaired in patients with HFpEF than in patients

with LV systolic dysfunction and atrial fibrillation,

with

(73)

but not with pulmonary artery systolic pressure

(Figure 2). Subtle RA deformation deterioration has

(PASP) (78). The contribution of atrial fibrillation to

also been appreciated more commonly in HFpEF

RV dysfunction is complex and independent of

RV

GLS

functions

asymptomatic

are

diastolic

more

dysfunction

RV

failure;

PH

however,

and

other

right

factors

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F I G U R E 3 Heat Map of Correlations Between Demographic, Laboratory, Conventional, and Speckle Tracking Echocardiography Variables

Phenotypic heat maps (phenomaps) are constructed from cluster analysis and can correlate many variables to form groups. This sample phenomap shows demographic, laboratory, TTE, and speckle tracking echocardiography variables integrated for 100 participants, each represented by a column. Elaborate dendrograms are formed clustering participants (columns) and variables (rows) in an unsupervised manner. STE ¼ speckle tracking echocardiography; TTE ¼ transthoracic echocardiography; other abbreviations as in Figure 2.

pulmonary pressures. Right atrial contractile and

RIGHT

reservoir functions are also impaired in HFpEF pa-

CAPACITY. Resting RVLS has been shown to be a

HEART

MECHANICS

AND

FUNCTIONAL

tients in sinus rhythm with a history of paroxysmal

good predictor of functional capacity in both HFrEF

atrial fibrillation compared to those without a history

and HFpEF (34). Decreased RV GLS and free wall

of atrial fibrillation (79).

longitudinal strain are better predictors of dyspnea

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and NYHA functional class status in HFpEF than conventional echocardiographic indices (80). Resting RV tissue Doppler systolic velocity, RV fractional area change (RV FAC), and pulmonary artery systolic pressure independently predict peak oxygen consumption in HFpEF patients undergoing cardiopulmonary stress testing (34). Exercise-induced LA dysfunction may play an important role in exerciseinduced RV dysfunction. Impaired LA reservoir response to exercise appears to be a key trigger for RV-PA

uncoupling

and

exercise

ventilatory

inefficiency (62). PROGNOSTIC VALUE OF RIGHT HEART MECHANICS.

Both conventional and deformation parameters are prognostically valuable (Table 3). FAC <35% was the

HIGHLIGHTS  HFpEF is a complex clinical entity that is poorly understood yet is present in up to 5.5% of the general population.  Assessment of myocardial mechanics provides unique insight into the pattern of the myocardial dysfunction observed during disease progression through preclinical and clinical HFpEF.  Novel phenotyping methods, including machine learning, can integrate these myocardial mechanics into clinical groups used to advise and treat patients.

strongest predictor of death in 1 HFpEF cohort undergoing extensive echocardiographic, invasive hemodynamic, and clinical follow-up (81). A large meta-analysis reported a reduction of TAPSE by 5 mm increased mortality by 26% (odds ratio: 1.26; 95% confidence interval [CI]: 1.16 to 1.38; p < 0.001) and a decrease in FAC by 5% increased mortality by 16% (odds ratio: 1.16; 95% CI: 1.08 to 1.24; p < 0.001) (68). Right atrium larger than LA, independently of LVEF, is associated with all-cause mortality in those hospitalized with HF (82). A TAPSE/PASP ratio, an estimate of RV-PA coupling <0.36 is a powerful independent predictor of all-cause mortality in the HFpEF population (83). Among patients with HFpEF, both the TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariate adjustment (78).

conventional statistical methods. Broadly, the algorithms can be divided into supervised learning, unsupervised learning, and reinforced learning. In supervised learning, the data are typically divided into training and testing sets for the algorithm to learn and validate the performance and accuracy of the model. The final algorithm can group an observation into 1 or more categories or outcomes. On the other hand, multivariate, unsupervised machine learning algorithms do not seek labeled outcomes in the data to assess the accuracy. Instead, it comports to naturally occurring patterns within the heterogenous data to discover hidden relationships between variables for effectively categorizing patients and predicting outcomes (88,89) (Figure 3). In HFpEF, specifically, a growing number of studies have shown success in formulating individualized phenotypes. In

DATA-DRIVEN APPROACHES IN HFpEF

2015, Shah et al. (75) used these techniques to identify 3 distinct phenotypes in an exploratory cohort of 397

HFpEF is a complex, nonlinear, multivariate problem

HFpEF

that demands a customizable approach for diagnosis

grouping abilities with echocardiographic parameters

patients.

Other

studies

showed

similar

and treatment of patients. Current assessment stra-

during exercise as well (90,91). More recently, Omar

tegies for diastolic dysfunction resort to 1-sided con-

et al. (92) constructed a 2-step clustering model with

ventional variable cutoff values for diagnosis and

speckle tracking echocardiography variables to divide

grading of severity (84). This design leaves opportu-

patients into 3 groups of worsening diastolic function

nities for improvement when taking into account the

and LV filling pressure (92).

conglomerate of mechanisms previously described

There is also the potential for tools to guide ther-

(85,86). Fortunately, along with the development of

apy for Stage A and B patients with comorbid het-

novel techniques such as speckle tracking echocar-

erogeneous disorders that have been historically

diography, technology for novel computing of big

difficult to diagnose. One study in 2015 formed phe-

data has evolved that can offer newer methods for

notypes for HFpEF risk factors which correlated with

data assessment (87).

worse cardiac mechanics. The study used agglomer-

Machine learning is 1 subfield of artificial intelli-

ative hierarchical clustering for phenomapping of

gence which aims to automatically learn from data,

1,273 patients from the HyperGEN (Family Blood

identify patterns, and make decisions with minimal

Pressure Program; NCT00005267) study, using 47

human intervention. Generally, machine learning

routine clinical and echocardiographic variables to

tends

formulate 2 distinct phenotypes of patients with

to

make

fewer

pre-assumptions

than

11

12

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Myocardial Mechanics in HFpEF

hypertension. The second phenogroup was found to

complexity of variables that affect the development

have significantly worse conventional and speckle

of HFpEF, a multiparametric approach is necessary.

tracking echocardiography cardiac mechanics, even

This creates a big-data problem that can be addressed

when correcting for a number of demographic and

using

laboratory data (93). Merging these advanced statis-

learning. Further understanding of the evolution and

tical methods with common technologies such as

heterogeneity

smartphone applications or internet websites may

bioinformatics-driven platforms have the capability

allow for user-friendly clinical integration and help

to identify individualized phenotypes and may

bridge the gap to every day clinical practice (94).

inform optimal treatment strategies. Certainly, given

Furthermore, the ready identification of clinical

the heterogeneity of HFpEF, there is an urgent need

phenotypes may aid in individualizing therapies and

for understanding the role of machine learning ap-

making predictions for individual patients (95).

data-driven of

analytics myocardial

including

machine

mechanics

using

proaches for recognizing specific HFpEF phenotypes for clinical trials. Moreover, automatic data collection

CONCLUSIONS

from electronic health records and cardiac images

HFpEF is common and poorly understood. Abnormal

with clinical risk factors, genomics, proteomics, and

myocardial mechanics evolve as a patient progresses

wearable devices may allow precise risk stratification.

using machine learning tools and supplementing it

from Stage A to D in the HF continuum. The devel-

Applying deep learning, a novel artificial intelligence

opment of HFpEF involves complex interactions,

technique based on neural network, also may provide

which include systolic and diastolic dysfunction

ample opportunities for classification and phenotypic

within multiple cardiac chambers. Certain deforma-

identification of the disease and requires careful

tion parameters conditionally deteriorate during ex-

considerations in future trials.

ercise. Although common mechanical changes are present, significant heterogeneity in structure and

ADDRESS FOR CORRESPONDENCE: Dr. Partho P.

function exist. In addition to multiple image bio-

Sengupta, West Virginia University Heart and Vascular

markers, heterogeneity of clinical features and

Institute, 1 Medical Center Drive, Morgantown, West

biochemical

Virginia

markers

compound

this

syndromes

complexity. Because of the high dimensionality and

26506-8059.

E-mail:

partho.sengupta@

wvumedicine.org. Twitter: @ppsengupta1.

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KEY WORDS deformation imaging, diastolic dysfunction, global longitudinal strain, heart failure with preserved ejection fraction, left atrial strain, left ventricular strain, myocardial strain, right ventricular strain